Discussion
In this study, 10.04% of our patients with cystic fibrosis underwent diagnostic work up due to symptoms suggesting any drug related hypersensitivity reaction and we confirmed drug allergy in 0.9% of the study population. Unlike previous studies, none of the children exhibited beta-lactam hypersensitivity, instead a non-beta lactam antibiotic, TMP/SMX was the culprit agent responsible for DHRs.
There is limited data concerning prevalence of confirmed DHRs in general population. Rebelo et al demonstrated parentally-reported drug allergy prevalence as 4.6% in children and diagnostic work up revealed confirmed drug allergy in 0.2% of the study population (19). In a population based study concerning school aged children, the true frequency of immediate type drug hypersensitivity was shown as 0.11% (20). In the present study, the prevalence of DHRs was similar to general population, however, lower than the prevalence of DHRs compared to some previous studies (28.8-61.9%) (7-9, 21).
Since there is contradictory results about the frequency of DHRs in the literature, we summarized these studies in Table 3 to make a comparison. In earlier studies, the prevalence of DHRs in patients with CF ranged between 28.8-61.9% (7-9, 21, 22). There might be a number of comments for this. The majority of patients with cystic fibrosis included were only adults or adults and children. Burrows et al demonstrated that the age of the patients with CF who experienced a DHR was older and a higher proportion of patients older than 25 years had DHRs compared with younger patients. Further, higher number of antibiotics courses were not associated only with higher risk of antibiotic allergy but also with allergy to more than one antibiotic (22). However, Roehmel et al showed that DHRs were drug-specific and dependent on cumulative annual dose (7). The definitions of DHRs might not fit all criteria for DHRs defined in guidelines. Pleasant et al described the DHRs as rash and drug induced fever in their study (8). Besides, the clinical presentations of DHRs were not detailed in most of these studies. Probably the most important problem in these studies was that the guidelines defined allergy assessment steps were not followed, and most studies were retrospective and based on questionnaires and / or medical records. Nevertheless, skin tests and DPTs were not performed for confirmation of true drug allergy (7-9, 21, 22). It is well-known that, minority of suspected DHRs were proved to be accurate drug allergy (19).
It is encouraging that our results are consistent with that found by Matar (11), Braun (12) and Caimmi (10) et al ranging between 0.71-2.3%. Caimmi et al. conducted skin tests and DPTs on 14% of 171 patients with suggestive DHR due to beta-lactam antibiotics and 2.3% of the study cohort was diagnosed as immediate type beta-lactam allergy (10). The reason for higher frequency of DHRs in cystic fibrosis has been argued that repetitive antibiotic administrations may result in increased risk of sensitization (7, 21, 22). Rather, recurrent exposure to drugs, especially by courses longer than applied to everyone might contribute to development of tolerance. Unfortunately, our patients also used antibiotics frequently. One fourth of our patients were hospitalized due to pneumonia which were treated by parenteral antibiotics within last year. Although we did not have the data related to the total number of antibiotic courses up to child’s age; in the last year, nearly all consumed antibiotics at least once and half of the cases used antibiotics more than twice.
One unanticipated finding was that there were no cases with beta-lactam allergy, besides two patients were diagnosed as TMP/SMX allergy (0.9%). Recently, in a population of 601 patients with cystic fibrosis, the prevalence of TMP/SMX hypersensitivity was indicated as 0.49% and found as the second class of antibiotics responsible for DHRs (12). Self-reported sulfa allergy ranged between 0.07-2.7% in different populations (23-25). Increased antigenicity to sulfamethoxazole in sulfamethoxazole-hypersensitive patients with cystic fibrosis was demonstrated. T cells from sulfamethoxazole-hypersensitive patients with cystic fibrosis were stimulated with oxidative metabolites of sulfamethoxazole more than sulfamethoxazole-hypersensitive patients without cystic fibrosis in terms of higher secretion of IFN-g, IL-6, and IL-10. Additionally, recurrent infections might enhance sulfamethoxazole metabolite formation, therefore increased protein adduct formation associated with the stimulation of sulfamethoxazole-responsive T cells (26). In view of the results of these studies, physicians dealing with cystic fibrosis should be more vigilant about DHRs due to TMP/SMX HRs which was an understudied area.
As far as we know, this is the first study which focused on prevalence of any drug hypersensitivity reaction in patients with cystic fibrosis. In the present work, we extensively inquired patients and reviewed medical records for DHRs related to drugs other than beta-lactam and non-beta lactam antibiotics. Due to chronic nature of cystic fibrosis, the patients frequently exposed not only to antibiotics but also NSAIDs, proton pump inhibitors and others (6). Use of the offending drug or cross-reactive ones in chronic or repetitive treatment schedules enhance the risk for DHRs. Actual drug allergy was shown to be more frequent in patients with chronic diseases (27, 28). However, we were unable to demonstrate hypersensitivity to drugs other than antibiotics.
There are some limitations of this study. We did not have detailed information about the classes of antibiotics and NSAIDs and duration of treatment courses used during lifetime. The study had both retrospective and prospective aspects that some of diagnostic tests might not have been done with optimum timing.
As adverse drug reactions accumulate over time, the physicians will try to manage their patients with CF with limited number of treatment options. Therefore, it is crucial to assess cases according to established diagnostic protocols. Numerous and long-term use of multiple drugs during management of cystic fibrosis may contribute to tolerance development and protect patients from actual drug allergy.